.beta.-lactames are enzymes which open the .beta.-lactam ring of such antibiotics as penicillins and cephalosporins to yield products which are devoid of antibacterial activity. Clavulanic acid or 3-(.beta.-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo [3,2,0]heptane-2-carboxylic acid, including its pharmaceutically acceptable salts and esters, has now been well-recognized as a medium potency antibiotic which inhibits the production of .beta.-lactame enzymes, thereby enhancing the efficacy of .beta.-lactam antibiotics.
In particular, the combination of clavulanic acid and amoxycillin has been shown to be particularly effective against .beta.-lactames. The latter antibiotic is usually combined in a relatively large weight excess with the clavulanic acid to yield various pharmaceutical compositions. Dry, unit-dose compressed tablets for oral administration are just one example of a suitable formulation. These are disclosed, for example, in WO 94/16696.
Unfortunately, in the preparation of many of these dry formulations the art has necessitated the inclusion of a complex formulation of excipients, including binders, glidants, disintegrants and even desiccants, etc. to yield a pharmaceutically acceptable carrier. This is in part due to the fact that clavulanate is a highly hygroscopic material which is highly unstable in aqueous media. Methods of formulation must therefore ensure that the product can retain its potency during storage, and yet can subsequently yield satisfactory dissolution rates. One such process is disclosed in WO 92/19227 and mandates the inclusion of both an intra-cellular and an extra-cellular disintegrant. Another process which is described in U.S. Pat. No. 4,537,887 specifies the inclusion of an edible desiccant within the composition itself. Other processes warrant the inclusion of a desiccant within a container housing the amoxycillin/clavulanate combination. In this regard, U.S. Pat. Nos. 4,301,149 and 4,441,609 are particularly salient.
Other preparations containing clavulanic acid derivatives and .beta.-lactams include liquid pharmaceutical suspensions prepared from dry powder or granulate compositions. Liquid suspensions are often preferred from a dosing standpoint as these are often easier to administer and are more palatable than dry pills. Children and the elderly especially benefit from medication delivered in this form. Examples of such preparations may be found in WO 96/34605. Dry formulations containing the active ingredients are first prepared, and these are then liquified with water or other suitable liquid, either at the manufacturing facility, the pharmacy, or by the consumer just prior to ingestion. Unfortunately, some of these preparations are still not acceptable because of problems associated with the storage of these dry powder compositions. Many simply do not have a suitable shelf life to make them commercially viable. Some, for example, do not seek to optimize the type of preservative which stabilizes and extends the shelf life of the suspension.
What is now needed in the art is an improved pharmaceutical composition containing a .beta.-lactam antibiotic such as amoxycillin and a .beta.-lactamase inhibitor such as clavulanic acid (clavulanate) which is easy to manufacture, provides a potent combination of the two active agents, and yet is storage stable over extended periods, is easily liquified with a suitable aqueous carrier, is highly palatable, and is easily ingested.